Use of dsrnas in strategic therapeutic intervention of highly active antiretroviral therapy

ABSTRACT

In the treatment of HIV administration of dsRNA at an appropriate stage in highly active antiretroviral (HAART) therapy of HIV allows for the discontinuation of HAART by increasing the time to HIV rebound after stopping HAART.

BACKGROUND OF THE INVENTION

Sixteen antiviral agents are currently approved by the FDA for thetreatment of HIV infection. All target the specific HIV enzymes, reversetranscriptase (RT) or protease. The use of various combinations of thesedrugs is referred to as highly active anti-retroviral therapy (HAART)and has provided dramatic decreases in morbidity and mortality of HIVinfection. Reduction of the plasma HIV RNA to undetectable levels inpatients with wildtype virus (i.e. non-RT or protease resistant) isroutinely possible with the appropriate application of HAART. Reductionof EIV loads potentially enables reconstitution of the immune system andled to early speculation that HIV could be eliminated by HAART.Subsequent experience has provided a more realistic view of HAART andthe realization that chronic HIV suppression using HAART, as currentlypracticed, would require treatment for life with its resultantsignificant cumulative toxicities. Moreover, chronic HAART results inloss of HIV-specific cytotoxic T-lymphocytes (CTL) and memory responses.

Chronic therapy with HAART is necessitated by integration of the HIV DNAprovirus in CD4+ resting memory cells that are not targets of HAARTuntil activation of replicating HIV. Because of the long half-life ofthese cells, current estimates suggest that it would require as many as60 years of HAART for elimination of HIV in the infected patient.Cumulative toxicities from HAART are currently a major contributor tonon-compliance and non-acceptance for such long-term treatmentrequirements. Moreover, non-compliance by patients results insub-optimum levels of HAART drugs which facilitates the development ofRT and protease resistant HIV mutants. Although more potent secondgeneration drugs are under development that target the RT and proteasegenes as well as new HIV targets, the problem of drug toxicities, thecomplex interactions between these drug classes, and the likelihood oflife-long therapy will remain a serious drawback to their usage. Therecent concept and limited experience with Strategic TherapeuticInterruption (STI) of HAART provides a unique opportunity to minimizethe current deficiencies of HAART while retaining the superb HIVsuppression capacities of HAART.

STI is the cessation of HAART for a prescribed period of time duringwhich HIV again becomes detectable (i.e. rebound) followed by resumptionof HAART with subsequent suppression of HIV. During HAART suppression ofHIV, the immune system becomes desensitized to HIV antigens presented byHLA I molecules. By allowing a transient rebound of HIV during the STIof HAART the immune system may become sensitized to the patient's ownvirus. By reinstitution of HAART, HIV is suppressed before it caninflict damage to the immune system TABLE 1 HAART-Based ToxicitiesPrinciple Serum Laboratory Principle Metabolic HAART Markers of CellAbnormality Components Toxicity Toxicity Phenotypic Effect Lipid StoragePI^(a) Cholesterol, Adipocytes Lipodystrophy^(d,e) triglycerides(peripheral fat wasting abdominal/dorsal cervical accumulation) GlucosePI C-peptide, Liver, Altered glucose Utilization insulin, glucose^(c)muscle metabolism insulin- resistant diabetes^(e) MitochondrialNRTI/NNRTI^(b) Lactic acid Variable Pancreatitis, Function neuropathy,myopathy, nephritis, osteopenia Hepatic PI/NRTI ALT, HBs HepatocytesSevere liver toxicity Membrane antigen, Integrity HCV RNA^(a)Protease inhibitors^(b)Nucleoside and non-nucleoside reverse transcriptase inhibitors^(c)Oral glucose tolerance test^(d)All PIs and some NRTIs induce lipodystrophy^(e)With chronic use there is potential for significant adverse effectson the cardiovascular system (ie; coronary and cerebral vascularthromboses)of the patient (i.e. destruction of the CD4+ T-cell helper function).The development of resistance to HAART components has not proven to be aproblem since selection pressure is removed by complete cessation ofHAART.

The concept of immunization with the patient's own HIV during STIoriginated from the observation of the clinical course of the “Berlinpatient” who was treated before complete treated with HAART early in thecourse of HIV infection in which CTL responses against gag antigens ofHIV were preserved by introduction of HAART early in the course ofinfection. Suppression of plasma HIV RNA following STI was associatedwith strong CTL responses. STI in patients not treated early with HAARTduring HIV infection have demonstrated less successful suppression ofHIV. Oritz et.al. report that two of six patients contained plasmavirermia for twelve and twenty-four months, respectively, following STIof HAART. Strong CTL responses correlated with suppression of viremia.Similarly, Lori et al. using hydroxycarbamide modified HAARTdemonstrated an 180 day suppression of viremia in one of three patients.The difference in response rates between early HAART versus treatmentstarted after complete seroconversion of Western blots would appear torelate to the preservation of CTL responses early in the course of HIVinfection as compared to their absence once HIV infection enters itschronic phase. Potentiation of the CTL response during STI would,therefore, be a desirable goal for maximizing immune responses tocontrol viremia and prolong HAART-free intervals since the expectedrelapse rate in just 30 days after stopping HAART is 86%.

DESCRIPTION OF THE INVENTION

We have found that the administration of dsRNA at an appropriate stagein HAART therapy allows for the discontinuation of HAART by increasingthe time to HIV rebound after stopping HAART. The dsRNA treatment leadsto a reduced incidence of toxicity to antiretroviral therapy and reducesthe overall costs associated with treating HIV infections.seroconversion of the Western blot response with a modified HAARTregimen with a reduction of plasma HIV load from 85,000 copies/ml toundetectable. During a temporary suspension of HAART, viremia occurredtransiently until resumption of HAART. During a second suspension ofHAART, no HIV rebound occurred. The patient elected to stop HAARTpermanently after 176 days with no subsequent viral rebound during thefollowing 551 days although traces of HIV RNA were detected in a lymphnode and replication competent virus was isolated from resting CD4+lymphocytes at very low frequencies. Thus, HIV in this patient had notbeen eradicated. Replication control was apparently provided by the cellmediated arm of the immune system since no neutralizing activity couldbe demonstrated and a strong CTL response to HIV p17 was observed. Thisobservation in a single patient, nevertheless, supports the argumentearlier (1997) suggesting increased focus on the cell-mediated arm ofthe immune system in order to control HIV infection. Recent studiesconfirm this insight and provide a rational mechanism for the role ofSTI in HAART.

A primary target for HIV is the CD4+ T-lymphocyte which accounts for itsdeclining numbers during the course of HIV infection and the naturalprogression to AIDS. Although CD8+ T-cytolytic lymphocytes are nottargets for HIV, their cytolytic capacity against infected cellspresenting HIV epitopes is dependent on functional help from CD4+ cells.Thus, the CTL response is disarmed by an attack on CD4+ lymphocytes.With the loss of HIV memory cells during infection by HIV, chronicsuppression of HIV by HAART provides no mechanism for the induction ofspecific CTL responses even with rising CD4+ levels. Rosenberg et.al.report the successful use of STI in five of eight patients who were

The invention includes methods of enhancing therapy against HIV byadministering to patients whose HIV plasma RNA has been suppressed byactive anti-retroviral therapy to a value below detection, typicallyless than 50 copies/ml, a synthetic, specifically configured,double-stranded ribonucleic acid (dsRNA) which retains theimmunostimulatory and antiviral properties of other double stranded RNAmolecules but exhibits greatly reduced toxicity. Concurrentanti-retroviral and dsRNA therapy is continued for a predeterminedperiod of time, for example 2-4 months, then anti-retroviral therapy isdiscontinued while dsRNA therapy is maintained then, following an HIVrebound the HAART is restarted. A rebound may be determined by HIVplasma RNA of more than 5,000 copies/ml for three consecutive weeks ormore than 50,000 copies/ml on a single occasion. While other indicatorsof HIV, presence/activity may be employed, such as change in CD4+lymphocyte count, we prefer assessing MV plasma RNA as being bothconvenient and accurate based on the sensitive assay for same currentlyavailable.

The dsRNA of choice is Ampligen®, a synthetic, specifically configured,double-stranded ribonucleic acid (dsRNA) which retains theimmunostimulatory and antiviral properties of other double-stranded RNAmolecules (dsRNA) but exhibits greatly reduced toxicity. Like otherdsRNA, Ampligen® can elicit the induction of interferon and othercytokines. Ampligen® has the ability to stimulate a variety ofdsRNA-dependent intracellular antiviral defense mechanisms including the2′,5′-oligoadenylate synthetase/RNase L and protein kinase enzymepathways.

The mismatched dsRNA may be of the general formula rI_(n)·r(C₁₂U)_(n).In this and the other formulae that follow r=ribo. Other mismatcheddsRNAs for use in the present invention are based on copolynucleotidesselected from poly (C_(n),U) and poly (C_(n)G) in which n is an integerhaving a value of from 4 to 29 and are mismatched analogs of complexesof polyriboinosinic and polyribocytidilic acids, formed by modifyingrI_(n)·rC_(n) to incorporate unpaired bases (uracil or guanine) alongthe polyribocytidylate (rC_(n)) strand. Alternatively, the dsRNA may bederived from r(I)·r(C) dsRNA by modifying the ribosyl backbone ofpolyriboinosinic acid (rI_(n)), e.g., by including 2′-O-methyl ribosylresidues. The mismatched may be complexed with an RNA-stabilizingpolymer such as lysine cellulose. Of these mismatched analogs ofrI_(n)·C_(n), the preferred ones are of the general formularI_(n)·r(C₁₁₋₁₄,U)_(n). or rI_(n)·r(C₂₉,G)_(n), and are described byCarter and Ts'o in U.S. Pat. Nos. 4,130,641 and 4,024,222 thedisclosures of which are hereby incorporated by reference. The dsRNA'sdescribed therein generally are suitable for use according to thepresent invention.

Other examples of mismatched dsRNA for use in the invention include:

-   r(I)·r(C₄, U)-   r(I)·r(C₇, U)-   r(I)·r(C₁₃, U)-   r(I)·r(C₂₂, U)-   r(I)·r(C₂₀, G) and-   r(I)·r(C_(p23),G_(>p)).

Alternatively the dsRNA may be the matched form, thus polyadenylic acidcomplexed with polyuridylic acid (poly A•poly U) may also be used.Clinical studies of Ampligen® have reported the following activities:decreases in viral load, stabilization of CD4 cell counts, andrestoration of delayed type hypersensitivity (DTH) in anergicindividuals infected with HIV. Despite the dramatic reduction of HIVload in patients on various highly active anti-retroviral therapy(HAART) regimens, the development of drug resistant mutants duringtherapy provides a significant challenge for long-term inhibition of HIVreplication. The recent demonstration of synergy between Ampligen® andall three classes of currently FDA-approved drugs and the ability toinhibit drug-resistant mutants from each class has renewed interest inAmpligen® as a potential new drug with a new mechanism of action toinhibit HIV replication. Moreover, the immunomodulatory activity ofAmpligen® suggests that the drug may function to reverse the Th1 to Th2switch observed with HIV infection. Natural killer (NK) cell activity isalso increased in Ampligen® treated nude mice bearing human bladdercarcinoma, renal carcinoma and melanoma xenografts. Similarly, humanPBMCs treated with Ampligen® respond with an increase in NK cellactivity.

The following table lists the FDA approved antiretroviral drugs and drugcombinations: TABLE 2 Antiretroviral Drugs and Drug CombinationsApproved by FDA for the HIV Indication as of Dec. 31, 2001 Abacavir(Ziagen) Amprenavir (Agenerase) Zidovudine (Retrovir) CombivirZalcitabine (Hivid) Lamivudine (Epivir) Didanosine (Videx) TrizivirStavudine (Zerit) Lopinavir (Kaletra) Efavirenz (Sustiva) Nevirapine(Viramune) Indinavir (Crixivan) Delavirdine (Resciptor) Ritonavir(Norvir) Saquinavir (Fortovase or Invirase) Nelfinavir (Viracept)Tenofovir (Viread)The present invention includes the above combinations as well as otherantiretroviral drugs and drug combinations yet to receive approval oracceptance in HAART.

Failure of antiretroviral therapies over time and the demonstration ofresistance have stimulated intensive searches for appropriatecombinations of agents, or sequential use of different agents, that actat the same or different viral targets. HAART is the utilization ofseveral antiretrovirals with different mechanisms of actions to decreaseviral loads in heavily experienced HIV-1 infected patients. Thisinvention demonstrates the effectiveness of adding Ampligen® to HAARTwith regard to the duration of antiviral response, assessed by plasmaHFV-1 RNA measurements (Roche Amplicor Assay) following a STI of HAART.

The use of dsRNAs as monotherapy in HIV disease is described in U.S.Pat. No. 4,820,696 and in combination with other anti-retroviral agentsis described in U.S. Pat. No. 4,950,652.

Clinical Examples

An open-label, prospective, randomized, controlled study of the safetyand biological effects, including clinical, immunologic, and virologicassessments, of adding Ampligen® 400 mg to a STI protocol of HAARTcontaining at least one of the following ten antiretroviral drugs:Ziagen (abacavir), Retrovir (zidovudine) AZT, Hivid (zalcitabine) ddC,Videx (didanosine) ddI, Zerit (stavudine) d4T, Sustiva (efavirenz),Crixivan (indinavir), Norvir (ritonavir) Viracept (nelfinavir), andAgenerase (amprenavir), in patients with plasma HIV RNA <50 and CD4levels ≧400.

Following Baseline evaluations (3 weeks) patients were stratified basedon the presence of one versus the presence of two or more of theabove-listed ten anti-retroviral drugs.

This study consisted of a period with a randomization (1:1/Ampligen®: NoAmpligen®) into two parallel arms with 60 patients receiving Ampligen®and 60 receiving no Ampligen®. Poly I:poly C₁₂U (200 mg) was given byintravenous infusions (IV) twice weekly for four doses (Weeks 1 and 2)and then 400 mg IV twice weekly thereafter. The no Ampligen® armreceived no IV infusions.

The primary study endpoint for efficacy is mean total time of theHAART-free intervals before rebound in plasma HIV-1 RNA (using the RocheUltra Sensitive assay). A secondary efficacy endpoint is change in CD4+lymphocyte count. Clinical status was followed. Safety and tolerancewere determined by documentation and analysis of the number, type,relatedness, and severity of adverse events; by the reasons for earlytreatment discontinuation; and by any trends in clinical laboratoryvalues indicating adverse effects.

All patients were on a HAART regimen that has suppressed HIV plasma RNAbelow the limits of detection (<50 copies/ml) during the last 9 monthsor longer. Following 8 weeks of Ampligen® or no Ampligen®, HAART wasdiscontinued and patients were monitored weekly for HIV rebound(i.e.—HIV plasma RNA)>5000 copies/ml for 3 consecutive weeks or >50,000on one occasion). Following HIV rebound, HAART is restarted. Eight (8)weeks after the plasma HIV RNA becomes undetectable, a second STI isintroduced and monitored identically to the initial STI.

Thirty day STI data from six patients enrolled in this study wereavailable. Three of these patients (coded S, W, and R in Table 3) wererandomized to receive Ampligen® and three of these patients (coded J, M,and D in Table 4 below) were randomized to not receive Ampligen®.

As can be seen from Tables 3 and 4, all patients met the entrancecriteria requiring a CD4 cell level >400, an HIV plasma RNA level <50copies/ml, and a HAART regimen containing at least one anti-retroviraldrug showing synergy with Ampligen® as listed above.

All patients were chronically HIV infected and were receiving theindicated HAART regimen prior to starting the STI. As shown in Table 4,during the first 30 days off of HAART, two of the three no Ampligen®patients relapsed with HIV plasma RNA levels increasing >1000 copies/mlcompared to no relapses in the Ampligen® cohort (Table 3). In order toobtain a better estimate of the expected rate of relapse of this patientpopulation when discontinuing HAART, a literature search andmeta-analysis was utilized. TABLE 3 Patient Characteristics AMP 720Study (Ampligen ®) CD4 Cell HAART¹ Patient Age Count HIV RNA Receivedbefore HIV Code (Years) Risk Factor (cells/mm³) (copies/ml) STI Relapse²S 58 Heterosexual 400 <50 3TC + ZDV + EFV No W 64 Homosexual 540 <503TC + ZDV + NVP No R 44 Heterosexual 890 <50 3TC + ZDV + NVP No¹ABC, abacavir; SQV, saquinavir; NVP, nevirapine; LPV, lopinavir; NFV,nelfinavir; 3TC, lamivudine; ZDV, zidovudine; EFV, efavirenz.²HIV Relapse = HIV RNA rebounded to ≧1000 copies/ml within first 30 daysof discontinuing HAART

TABLE 4 Patient Characteristics AMP 720 Study (No Ampligen ®) CD4 CellHIV RNA Patient Age Count (copies/ HAART¹ Received HIV Code (Years) RiskFactor (cells/mm³) ml) before STI Relapse² J 33 Homosexual 960 <50 3TC +ZDV + EFV Yes M 42 Homosexual 700 <50 ABC ÷ ZDV + 3TC + NFV No D 51Homosexual 530 <50 ABC ÷ LPV + SQV Yes¹ABC, abacavir; SQV, saquinavir; NVP, nevirapine; LPV, lopinavir; NFV,nelfinavir; 3TC, lamivudine; ZDV, zidovudine; EFV, efavirenz.²HIV Relapse = HIV RNA rebounded to ≧1000 copies/ml within first 30 daysof discontinuing HAART

Meta-analysis is a quantitative approach for systematically combiningthe results of previous research and has become a popular technique invirtually every area of medicine. A search of the biomedical Literaturewas conducted to identify publications which contained data pertainingto the rate of HIV relapse during STIs of HAART in chronically infectedHIV patients with CD4 cell levels ≧400 and HIV RNA plasma levels <50prior to initiation of the STI. Two recent publications were identifiedwhich studied HIV relapse rates during the first 30 days following thestart of the STI: Ruiz et al “HIV dynamics and T-cell immunity afterthree structured treatment interruptions in chronic HIV-1 infection”AIDS 2001, 15:F19-F27 and Birk et al “Kinetics of HIV-1 RNA andresistance-associated mutations after cessation of antiretroviralcombination therapy” AIDS 2001, 15:1359-1368.

Study A, Ruiz et al, from the Hospital Universitari Germans Trias iPujol, Badalona, Spain; Hôspital Pitié-Salpêtrière, Paris, France; andthe Centre for HIV Research, Edinburgh, Scotland, UK examined HIVdynamics after structured treatment interruptions (STIs) in chronicHIV-1 infection. As shown in Table 5, all 12 patients had HIV plasma RNAlevels <50 copies/ml, a CD4 level ≧400, and a HAART regimen containingat least one anti-retroviral drug showing synergy with Ampligen®. Ten ofthe 12 patients (all except patients 9 and 12) relapsed during the first30 days off HAART with HIV plasma RNA increasing above 1000 copies/ml.

Study B, Birk et al, from the Karolinska Institute, Huddinge UniversityHospital, Stockholm, Sweden also examined the kinetics of HIV-1 RNAchanges following the cessation of HAART. Of the 26 chronically infectedpatients studied, only nine of these patients had CD4 cell levels ≧400and HIV plasma RNA levels <50 prior to start of the STI. These ninepatients also had a HAART regimen containing at least oneanti-retroviral drug showing synergy with Ampligen®. Data on these ninepatients are shown in Table 6. Patient U was the only patient who didnot relapse with IV plasma RNA increasing to ≧1000 copies/ml within thefirst 30 days after initiation of the STI.

The combined data from Studies A and B yield a relapse rate of 86%(18/21) within the first 30 days of stopping HAART in chronicallyinfected HIV patients.

A meta-analysis combining the data from studies A and B with the interimresults of AMP 720 is shown in Table 7. TABLE 5 Patient CharacteristicsStudy A¹ Patient CD4 Cell Count HIV RNA HAART² Received Code Age (Years)Risk Factor⁴ (cells/mm³) (copies/ml) before STI HIV Relapse³  1 33 IVDU2870 <50 3TC + d4T + IDV Yes  2 37 IVDU 742 <50 ZDV + ddI + IDV + HU Yes 3 29 IVDU 1673 <50 3TC + d4T + IDV Yes  4 32 Heterosexual 1141 <503TC + d4T + NFV Yes  5 41 IVDU 1189 <50 3TC + d4T + NFV Yes  6 39Heterosexual 828 <50 3TC + d4T + SQV Yes  7 28 Heterosexual 1311 <503TC + d4T + IDV Yes  8 29 Heterosexual 1837 <50 3TC + d4T + IDV Yes  927 Heterosexual 1349 <50 3TC + d4T + IDV No 10 38 Homosexual 1486 <503TC + d4T + IDV Yes 11 38 Homosexual 1002 <50 3TC + d4T + IDV Yes 12 42IVDU 979 <50 3TC + d4T + RTV No¹AIDS 15: F19-F27 (2001)²d4T, stavudine; ddI, didanosine; HU, hydroxyurea; IDV, indinavir; NFV,nelfinavir; RTV, ritonavir; SQV, saquinavir; 3TC, lamivudine; ZDV,zidovudine.³HIV Relapse = HIV RNA rebounded to ≧1000 copies/ml within first 30 daysof discontinuing HAART⁴IVDU, intravenous drug user.

TABLE 6 Patient Characteristics Study B¹ CD4 Cell Count HIV RNA HAART²Received Patient Code Age (Years) Risk Factor⁴ (cells/mm³) (copies/ml)before STI HIV Relapse³ D 32 Homosexual 500 <50 ddI, EFV, d4T Yes F 42IVDU 550 <50 3TC, d4T, NFV Yes L 34 Heterosexual 580 <50 d4T, 3TC, NFVYes M 25 Heterosexual 760 <50 ZDV, 3TC, ddI Yes Q 61 Homosexual 710 <50d4T, ddI, RTV, IDV Yes T 56 IVDU 400 <50 d4T, 3TC, NFV Yes U 43Heterosexual 1410 <50 ZDV, 3TC, EFV No V 42 Homosexual 500 <50 d4T, 3TC,IDV, RTV Yes Y 41 Heterosexual 520 <50 d4T, 3TC, NFV Yes¹AIDS 15: 1359-1368 (2001)²d4T, stavudine; ddI, didanosine; IDV, indinavir; NFV, nelfinavir; RTV,ritonavir; 3TC, lamivudine; ZDV, zidovudine; EFV, efavirenz.³HIV Relapse = HIV RNA rebounded to ≧1000 copies/ml within first 30 daysof discontinuing HAART⁴IVDU, intravenous drug user

The meta-analysis (Table 7) shows that the 0% relapse rate for theAmpligen® cohort following the STI of HAART is significantly lower(p=0.012) than expected for this chronically infected population. TABLE7 Meta-Analysis of AMP 720 Interim Results Showing a Decreased HIVRelapse Rate with Ampligen ® Treatment No Relapses - Relapses -Treatment # Patients (%) # Patients (%) p-value* Ampligen ® 3 (100%)  0(0%) 0.012 No Ampligen ® 4 (16.7%) 20 (83.3%)*Fisher's Exact Test

A safety analysis summarized in the attached Table 8 shows no evidenceof increased toxicity. Blood laboratory studies at Week 8 were comparedto Baseline values for the Ampligen® and no Ampligen® cohorts. As can beseen in Table 8 there was no evidence of any added toxicity to the bonemarrow, kidneys, or liver by the addition of Ampligen® to the patient'sHAART regimen. Thus, these data suggest that the clinical benefit ofAmpligen® treatment can be obtained without any significant additionaltoxicity. TABLE 8 Ampligen ® Plus HAART Shows No Evidence of ToxicityAmpligen Mean Mean Mean Change Parameter Normal Ranges Treatment BSL*Week 8 Week 8 - BSL p-value⁺ Hemoglobin 12.5-17.0 g/dL YES 13.5 13.1−0.4 0.946 NO 14.5 14.0 −0.4 White Blood Count 4.0-10.5 × 10⁻³ /uL YES5.5 4.9 −0.6 0.726 NO 7.2 6.1 −1.1 Platelet Count 140-415 × 10⁻³ /uL YES271.4 241.0 −30.4 0.102 NO 281.7 281.7 0.0 Creatinine 0.5-1.5 mg/dL YES0.8 0.7 −0.1 0.270 NO 1.1 1.0 0.0 BUN 5-26 mg/dL YES 14.5 13.7 −0.80.342 NO 14.0 15.7 1.7 Gamma-GT 0-65 IU/L YES 64.8 74.3 9.5 0.758 NO58.3 77.0 18.7 SGPT(ALT) 0-40 IU/L YES 46.0 42.7 −3.3 0.304 NO 37.5 45.78.2 Alkaline 25-150 IU/L YES 105.7 89.0 −16.7 0.316 Phosphatase NO 109.8102.3 −7.5 Bilirubin, Total 0.1-1.2 mg/dL YES 0.4 0.3 −0.1 0.529 NO 0.50.5 0.0*BSL = Baseline + t-test (two-sided)

1. A method of mitigating the adverse effects of antiviral agents in HIVtherapy comprising administering to an HIV-infected subject at least oneantiviral agent until HIV is suppressed, discontinuing antiviraltherapy, administering a dsRNA, then, when HIV values increase resumingantiviral treatment with the at least one antiviral agent.
 2. he methodof claim 1 wherein step a dsRNA is administered with said antiviralagent.
 3. The method of claim 1 or wherein step HIV values aresuppressed to a value below detection.
 4. The method of claim 3 whereinthe value is less than 50 copies/ml of HIV plasma RNA.
 5. The claim 1wherein two or more anti-retroviral agents are used.
 6. The method ofclaim 5 wherein the anti-retroviral drug is selected from abacavir,amprenavir, zidovudine, combivir, zalcitabine, lamivudine, didanosine,trizivir, stavudine, lopinavir, efavirenz, nevirapine, indinavir,delavirdine, ritonavir, saquinavir, nelfinvir and tenofovir.
 7. Themethod of claim 1 where the dsRNA is rI_(n) r(C₁₂U)_(n), Poly A Poly Uor rI_(n r(C) ₂₉,G)_(n), in which r is ribo and n has a value of 4 to29.